Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteasome inhibitor bortezomib is emerging as a potent anti-cancer agent. Still, recent clinical trials have revealed a significant secondary toxicity of bortezomib. Consequently, there is much interest in dissecting the mechanism of action of this compound to rationally improve its therapeutic index. The cytotoxic effect of bortezomib is frequently characterized by interfering with downstream events derived from the accumulation of proteasomal targets. Here we identify the first chemical agent able to act upstream of the proteasome to prevent cell killing by bortezomib. Specifically, we show that the polyhydroxyl compound Tiron can function as a competitive inhibitor of bortezomib. This effect of Tiron was surprising, since it is a classical radical spin trap and was expected to scavenge reactive oxygen species produced as a consequence of bortezomib action. The inhibitory effect of Tiron against bortezomib was selective, since it was not shared by other antioxidants, such as vitamin E, MnTBAP, L-N-acetyl-cysteine, and FK-506. Comparative analyses with nonboronated proteasome inhibitors (i.e. MG132) revealed a specificity of Tiron for bortezomib. We exploited this novel feature of Tiron to define the "point of no return" of proteasome inhibition in melanoma cells and to block cell death in a three-dimensional model of human skin. Cells from T-cell lymphoma, breast carcinoma, and non-small cell lung cancer were also responsive to Tiron, suggesting a broad impact of this agent as a bortezomib blocker. These results may have important implications for the analysis of bortezomib in vivo and for the design of drug mixtures containing proteasome inhibitors.
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PMID:Chemical blockage of the proteasome inhibitory function of bortezomib: impact on tumor cell death. 1627 10

Sampangine is a plant-derived copyrine alkaloid extracted from the stem bark of Cananga odorata. This azaoxoaporphine alkaloid primarily exhibits antifungal and antimycobacterial activities but also displays in vitro antimalarial activity against Plasmodium falciparum and it is cytotoxic to human malignant melanoma cells. Recently, sampangine was described as a pro-apoptotic agent, but the biochemical pathway leading to cell death remained unclear. Considering that sampangine possesses an iminoquinone moiety, potentially functioning as an oxidizing agent, we have investigated the implication of an oxidant stress on sampangine-induced cytotoxicity. We show that the treatment of human HL-60 leukemia cells for 48 h with sampangine induced an important oxidative burst. Real time flow cytometry measurements indicated that the production of oxidative species is very rapid, within minutes following the drug addition. Quenching of reactive oxygen species by the antioxidants N-acetyl cystein, vitamin C and vitamin E abolishes the pro-apoptotic activity of sampangine. The drug-induced production of reactive oxygen species is associated with cell cycle perturbations and mitochondrial alterations. This study shed light on the mechanism of action of sampangine and provides novel opportunities to use azaoxoaporphine alkaloids as lead compounds for the design of pro-apoptotic anticancer agents.
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PMID:Induction of apoptosis by the plant alkaloid sampangine in human HL-60 leukemia cells is mediated by reactive oxygen species. 1628 42

Previous studies have demonstrated that treatment with activin A and TGF-beta(1), members of the TGF-beta family, stimulated maturation of mouse bone marrow-derived cultured mast cells (BMMC), which was characterized by morphology and gene expression of mouse mast cell proteases (mmcps). In order to gain a better understanding of activin A- and TGF-beta(1)-induced maturation in mast cells, we investigated the genes that were up-regulated in response to treatment with these two members of the TGF-beta family. The cDNA microarray analyses indicated that in BMMC, five genes were induced by treatment with 4 nM activin A for 2 h. Tocopherol-associated protein (Tap) was one of the induced genes, and the Tap induction in response to activin A treatment was confirmed by real-time RT-PCR analyses. Treatment with TGF-beta(1) at 200 pM but not BMP-2 at 4 nM also increased Tap gene transcript in BMMC. Activin A-induced Tap expression was detected in BMMC but not in RAW264 macrophage-like cells, B16 melanoma cells or P19 embryonic carcinoma cells. Treatment with >1 muM SB431542, an inhibitor of activin and TGF-beta type I receptors ALK4/5, reduced responsiveness of Tap expression to TGF-beta(1), whereas <0.5 microM SB431542 effectively reduced TGF-beta(1)-induced expression of mmcp-1 and mmcp-7. These results suggest that inhibitory effects of SB431542 are different between TGF-beta-induced genes. Reporter assays indicated that Tap expression enhances transcription mediated by the activin/TGF-beta pathway. Thus, the present results suggest that Tap induction in response to activin/TGF-beta occurs predominantly in mast cells and serves as a positive regulator in activin/TGF-beta signaling.
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PMID:Identification of tocopherol-associated protein as an activin/TGF-beta-inducible gene in mast cells. 1687 93

Poly (aspartic acid-co-lactic acid) (PAL) has been investigated as a new biodegradable material for Drug Delivery Systems (DDS). Similar to the poly (lactic acid-co-glycolic acid) (PLGA) nanospheres, the PAL nanospheres can control-release encapsulated drugs by hydrolysis and adhere to the mucous membranes to improve the drug absorption. In this study, the vitamin encapsulated PAL nanospheres were applied on mice to examine their effect on tumor metastasis and safety as an injectable DDS material for anti-cancer and other drugs. In the experiment, 6 C57BL/6 mice per group were intravenously administered with B16BL6 melanoma cells (1 x 10(5) per mouse) and non-encapsulated PAL nanospheres or pro-vitamin encapsulated nanospheres respectively, while the control group was administered with B16BL6 cells alone. Two weeks later, the lungs of the mice were excised and metastatic foci on the lung surface were counted. The melanoma cell metastasis to lungs was prevented by intravenous co-injection of B16BL6 melanoma cells with 1.7 microg of pro-vitamin E encapsulated PAL nanospheres. Its metastatic foci count (mean +/- SD) was 127+/-80, which was better than the control (246+/-95, p<0.02). Also, applying the pro-vitamin C and pro-vitamin A encapsulated PAL nanospheres as well as the non-encapsulated PAL nanospheres slightly decreased the number of metastasis colonies in the lungs as compared to that of the control. These results suggested that PAL nanospheres did not promote the lung metastasis of B16BL6 melanoma cells. Thus, the PAL nanospheres are safe material for injection applications.
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PMID:The effect of poly (aspartic acid-co-lactic acid) nanospheres on the lung metastasis of B16BL6 melanoma cells by intravenous administration. 1708 40

Indole-3-acetic acid (IAA) activation by horseradish peroxidase (HRP) has been suggested as a new cancer therapy. Interestingly, we found that ultraviolet B UVB radiation also can activate IAA and produce free radicals in a dose-dependent manner. In this study, we attempted to identify the free radicals generated by UVB-irradiated IAA (IAAUVB), and to determine whether IAAUVB can induce the apoptosis of G361 human melanoma cells. Since IAA/HRP produces reactive oxygen species (ROS), we examined whether IAAUVB-generated radicals include ROS. Our results show that IAAUVB-induced free radical production is not inhibited by catalase, superoxide dismutase, or sodium formate, indicating that ROS are not generated by IAAUVB. On the other hand, IAAUVB caused lipid peroxidation, and this was blocked by Trolox, a water-soluble vitamin E derivative. Moreover, we found that IAAUVB caused apoptotic cell death and that this was inhibited by a low temperature. We further investigated IAAUVB-mediated apoptotic pathways, and found that IAAUVB causes caspase-8, Bid, caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage. In addition, these apoptotic pathways were also blocked by low temperature. From these results, we propose that IAAUVB-induced free radicals cause human melanoma cell apoptosis via a death receptor-mediated apoptotic pathway.
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PMID:Light-activated indole-3-acetic acid induces apoptosis in g361 human melanoma cells. 1714 72

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the membrane anchorage and biologic functions of growth-related proteins. Contrary to preclinical studies showing the growth-suppressive activity of statins, competitive inhibitors of HMG CoA reductase, clinical application of statins in cancer is precluded by their lack of activity at levels prescribed for the prevention of cardiovascular disease and by their dose-limiting toxicities at high doses. The dysregulated and elevated HMG CoA reductase activity in tumors retains sensitivity to the isoprenoid-mediated posttranscriptional down-regulation, an action that complements the statin-mediated inhibition and may lead to synergistic impact of blends of isoprenoids and lovastatin on tumor HMG CoA reductase activity and consequently tumor growth. d-gamma- and d-delta-tocotrienols, vitamin E isomers containing an isoprenoid moiety, and lovastatin-induced concentration-dependent inhibition of the 48-hr proliferation of murine B16 melanoma cells with IC50 values of 20 +/- 3, 14 +/- 3, and 1.5 +/- 0.4 microM respectively. A blend of lovastatin (1 microM) and d-gamma-tocotrienol (5 microM) totally blocked cell growth, an impact far exceeding the sum of inhibitions induced by lovastatin (12%) and d-gamma-tocotrienol (8%) individually. Synergistic impact of these two agents was also shown in human DU145 prostate carcinoma and human A549 lung carcinoma cells. C57BL6 mice were fed diets supplemented with 12.5 mg lovastatin/kg body weight, 62.5 mg d-delta-tocotrienol/kg body weight, or a blend of both agents for 22 days following B16 cell implantation; only the latter had significantly lower tumor weight than those with no supplementation. Co-administration of isoprenoids that posttranscriptionally down-regulate tumor reductase may lower the effective dose of statins and offer a novel approach to cancer chemo-prevention and/or therapy.
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PMID:Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. 1739 88

This research aimed to test whether supplementation with a combination of antioxidant vitamins and minerals could reduce the risk of skin cancers (SC). It was performed within the framework of the Supplementation in Vitamins and Mineral Antioxidants study, a randomized, double-blinded, placebo-controlled, primary prevention trial testing the efficacy of nutritional doses of antioxidants in reducing incidence of cancer and ischemic heart disease in the general population. French adults (7876 women and 5141 men) were randomized to take an oral daily capsule of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 microg selenium, and 20 mg zinc) or a matching placebo. The median time of follow-up was 7.5 y. A total of 157 cases of all types of SC were reported, from which 25 were melanomas. Because the effect of antioxidants on SC incidence varied according to gender, men and women were analyzed separately. In women, the incidence of SC was higher in the antioxidant group [adjusted hazard ratio (adjusted HR) = 1.68; P = 0.03]. Conversely, in men, incidence did not differ between the 2 treatment groups (adjusted HR = 0.69; P = 0.11). Despite the small number of events, the incidence of melanoma was also higher in the antioxidant group for women (adjusted HR = 4.31; P = 0.02). The incidence of nonmelanoma SC did not differ between the antioxidant and placebo groups (adjusted HR = 1.37; P = 0.22 for women and adjusted HR = 0.72; P = 0.19 for men). Our findings suggest that antioxidant supplementation affects the incidence of SC differentially in men and women.
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PMID:Antioxidant supplementation increases the risk of skin cancers in women but not in men. 1842 10

Honokiol, a compound extracted from Magnolia officinalis, has antitumor and antiangiogenic properties in several tumor models in vivo. Among the downstream pathways inhibited by honokiol is nuclear factor kappa beta (NFkappabeta). A prime physiologic stimulus of NFkappabeta is reactive oxygen species. The chemical structure of honokiol suggests that it may be an effective scavenger of reactive oxygen species. In this work, we have studied the reactions of honokiol with superoxide and peroxyl radicals in cell-free and cellular systems using electron spin resonance (ESR) and high-performance liquid chromatography (HPLC) techniques. Honokiol efficiently scavenged superoxide radicals in xanthine oxidase and cytochrome P-450 cell-free systems with the rate constant 3.2x10(5)M(-1)s(-1), which is similar to reactivity of ascorbic acid but 20-times higher than reactivity of vitamin E analog trolox. Honokiol potently scavenged intracellular superoxide within melanoma cells. In addition, honokiol scavenged peroxyl radicals generated by 2,2'-azo-bis(2-amidinopropane hydrochloride) (AAPH). The rate constant of the reaction of honokiol with peroxyl radicals (1.4x10(6)M(-1)s(-1)) was calculated from the competition with spin trap 5-(ethoxycarbonyl)-5-methyl-1-pyrroline N-oxide (EMPO), and was found close to reactivity of trolox (2.5x10(6)M(-1)s(-1)). Therefore, honokiol is an effective scavenger of both superoxide and peroxyl radicals, which may be important for physiological activity of honokiol.
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PMID:Honokiol is a potent scavenger of superoxide and peroxyl radicals. 1864 Jan 1

The effect of eight vitamin E analogues (d-alpha-, dl-alpha-, d-beta-, d-gamma-, and d-delta-tocopherols, d-alpha- and dl-alpha-tocopheryl acetates) and 2,2,5,7,8-pentamethyl-6-hydroxychroman (PMC) on melanogenesis were compared in mouse B16 melanoma cells. D-beta-tocopherol at 250 mug ml(-1) inhibited not only 28% of melanin synthesis in B16 cells, but also 34% of the tyrosinase activity, a very important cascade enzyme involved in the synthesis of melanin in melanoma cells. D-gamma-tocopherol also strongly inhibited up to 39% of melanin synthesis and 45% of the tyrosinase enzyme activity at the same concentration. The inhibitory activity of both d-beta- and d-gamma-tocopherols was observed without cytotoxicity up to a concentration of 250 mug ml(-1). Weak activity was also observed with d-delta-tocopherol at 8 mug ml(-1) and with PMC at 16 mug ml(-1), with 19% and 25% inhibition of melanin synthesis, respectively. However, PMC did not directly inhibit tyrosinase, as was observed with d-beta-, d-gamma-, and d-delta-tocopherols. Analysis by reverse transcription-polymerase chain reaction showed that the mechanism of melanogenesis inhibition by d-beta- and d-gamma-tocopherols in cells might be attributed to reduced expression of tyrosinase and tyrosinase related protein-2 mRNA in addition to direct inhibition of the tyrosinase. These findings suggest that both d-beta-tocopherol and d-gamma-tocopherol might be useful as effective ingredients in whitening cosmetics with lower skin toxicity to prevent or improve skin pigmentation such as skin spots and freckles caused by UV exposure.
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PMID:Comparison of the inhibitory effects of vitamin E analogues on melanogenesis in mouse B16 melanoma cells. 1956 43

Chemotherapy resistance and related defects in apoptotic signaling are crucial for the high mortality of melanoma. Effective drugs are lacking, also due to the fact that apoptosis regulation in this tumor is essentially not understood. The cytosine analogue ferropoptoside (N69), which contains an iron carbonyl complex, resulted in strong induction of apoptosis in melanoma cells starting already after 2h, whereas cytotoxicity remained at a low level. Surprisingly, there was no indication for any caspase activation at early times, although cytochrome c was released from mitochondria. Indicative for new proapoptotic pathways was the production of reactive oxygen species (ROS) as an early effect, and the inhibition of apoptosis by the antioxidant vitamin E. Apoptosis was also blocked by exogenous Bcl-2 overexpression and by the pan-protease inhibitor zVAD. However, only zVAD also prevented ROS production, for which Bcl-2 remained without an effect. Thus, new proapoptotic pathways are described here for melanoma cells clearly related to ROS production. A cascade enclosing enhanced levels of intracellular iron, which lead to enhanced ROS production in a Fenton reaction, appears as suggestive. Whereas off-target effects of zVAD appear as upstream, Bcl-2 may exert its inhibitory activity downstream of ROS. New proapoptotic pathways are of particular interest for melanoma as they may open new options for targeting this highly therapy-refractory tumor.
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PMID:New caspase-independent but ROS-dependent apoptosis pathways are targeted in melanoma cells by an iron-containing cytosine analogue. 1979 74


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